The present invention relates to an improved method for preparing certain aryl ethers that are useful as antidepressants. The invention also relates to intermediates useful in the method, and to methods for preparing such intermediates.
U.S. Pat. No. 4,229,449, issued Oct. 21, 1980, discloses compounds of formula (A) 
wherein
n and n1 are, independently, 1, 2 or 3;
each of the groups R and R1, which may be the same or different, is hydrogen; halogen; halo-C1-C6alkyl; hydroxy; C1-C6alkoxy; C1-C6alkyl optionally substituted; aryl-C1-C6alkyl optionally substituted; aryl-C1-C6alkoxy optionally substituted; xe2x80x94NO2; NR5R6 wherein R5 and R6 are, independently, hydrogen or C1-C6 alkyl, or two adjacent R groups or two adjacent R1 groups, taken together, form a xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 radical;
R2 is hydrogen; C1-C12alkyl optionally substituted, or aryl-C1-C6alkyl;
each of the groups R3 and R4, which may be identical or different, is hydrogen, C1-C6alkyl optionally substituted, C2-C4alkenyl, C2-C4alkynyl, aryl-C1-C4alkyl optionally substituted, C3-C7cycloalkyl optionally substituted, or R3 and R4 with the nitrogen atom to which they are bounded form a pentatomic or hexatomic saturated or unsaturated, optionally substituted, heteromonocyclic radical optionally containing other heteroatoms belonging to the class of O, S and N;
or R2 and R4, taken together, form a xe2x80x94CH2xe2x80x94CH2xe2x80x94 radical;
or a pharmaceutically acceptable salt thereof.
The compounds are disclosed to possess antidepressant activity.
In particular, U.S. Pat. No. 4,229,449 discloses the compound: 2-[xcex1-(2-ethoxyphenoxy)benzyl]morpholine: 
and pharmaceutically acceptable salts thereof, which possess useful antidepressant properties. This compound is also known as Reboxetine.
As illustrated in FIG. 4, U.S. Pat. No. 5,068,433 (issued Nov. 26, 1991) and related U.S. Pat. No. 5,391,735 (issued Feb. 21, 1995) disclose processes and intermediates useful for preparing single diastereomers of compounds of formula VIb: 
wherein R is C1-C6 alkoxy or tri-halomethyl. These diastereomers are disclosed to be useful intermediates for preparing compounds of formula A, including Reboxetine. The processes disclosed in these patents and in U.S. Pat. No. 4,229,449, however, are inefficient and provide a low overall yield of compounds of formula A when carried out on a commercial scale. Additionally the processes require the use of expensive reagents and require significant production times. Thus, it is not economical to prepare compounds of formula A on a commercial scale using the processes disclosed in these patents.
Accordingly, there is currently a need for improved processes for preparing compounds of formula (A), and for preparing intermediates useful for preparing compounds of formula (A). Ideally, the improved processes should utilize inexpensive reagents, be faster to carry out, or provide improved intermediate or overall yields compared to existing processes. Such improvements would facilitate the commercial scale production of compounds of formula (A).
As illustrated in FIG. 2, the invention provides a method for preparing an amine of formula VIIa: 
comprising:
a) oxidizing an optionally substituted trans-cinnamyl alcohol to give an intermediate epoxide of formula Ia: 
b) reacting the epoxide with an optionally substituted phenol to give a diol of formula IIa: 
c) reacting the diol with a silylating reagent to give an alcohol of formula IIa: 
xe2x80x83wherein P is a silyl-linked radical;
d) reacting the alcohol of formula IIIa with reactive derivative of a sulfonic acid to give a compound of formula IVa: 
xe2x80x83wherein Ra is a residue of a sulfonic acid;
e) removing P from the compound of formula IVa to give an alcohol of formula Va: 
f) displacing the sulfonyloxy group to give an epoxide of formula VIa: 
xe2x80x83and
g) reacting the epoxide with ammonia to give the compound of formula VIIa.
As illustrated in FIG. 3, the invention also provides a method further comprising:
h) reacting a compound of formula VIIa: 
xe2x80x83with a carboxylic acid of formula HOOCCH2L or a reactive derivative thereof, wherein L is a leaving group, to give an amide of formula VIIIa: 
i) reacting the compound of formula VIIIa to give a compound of formula IXa: 
xe2x80x83and
j) reducing the compound of formula IXa to give a corresponding compound of the following formula: 
The invention also provides novel intermediates disclosed herein (e.g. compounds of formulae III, IV, V, IIIa, IVa, and Va) as well as methods for their synthesis.